TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection, 2019, Zehn et al

Andy · Jun 18, 2019

Cytotoxic T-cells are essential mediators of protective immunity to viral infection and malignant tumors and are a key target for immunotherapy approaches. However, prolonged exposure to cognate antigen often attenuates the effector capacity of T-cells and limits their therapeutic potential1–4. This process, known as T-cell exhaustion or dysfunction1, is manifest through epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and up-regulate the expression of inhibitory receptors such as Programmed Cell-Death 1 (PD-1)5–8. Thus far, the underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T-cells are vaguely understood9–12.

Here we report that the development and maintenance of exhausted T-cell populations requires the thymocyte selection-associated high mobility group-box protein (Tox)13,14. Tox is induced by high antigen T-cell receptor stimulation and correlates with the presence of an “exhausted” phenotype during chronic Lymphocytic choriomeningitis virus and human hepatitis C virusinfection. Removal of its DNA-binding domain reduces PD-1 expression, augments cytokine production, and results in a more polyfunctional T-cell phenotype. Such mutated T-cells initially mediate increased effector function and cause more severe immunopathology but ultimately undergo a massive decline in their quantity, notably among the subset of Tcf1+ self-renewing T cells.

Altogether, we establish Tox as a critical factor for the normal progression of T-cell dysfunction, for the maintenance of exhausted T-cells during chronic infection, and we document a link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology.
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Paywall, https://www.nature.com/articles/s41586-019-1326-9
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TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection, 2019, Zehn et al

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TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection, 2019, Zehn et al

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